Project summary/abstract In the US, ?160,000 people per year develop heart failure from acute heart damage, mostly from heart attacks. Approximately 50% of them die within 5 years of the heart failure diagnosis. Currently, there are no therapies to prevent the development of heart failure after acute heart damage. A growing body of evidence points at Pirfenidone, a pyridone currently approved for the treatment of a rare disease through an unknown mechanism of action, as a powerful cardioprotective drug. Pirfenidone is a poorly tolerated drug because of its unfavorable pharmacokinetics. Innovative research recently conducted at Washington University in St Louis discovered that Pirfenidone protects the heart through an immunomodulatory effect on B lymphocytes. Pinpointing the cellular target of Pirfenidone, this research created the opportunity to optimize Pirfenidone. We expect that PEGylation of Pirfenidone with small PEG chains (<500 Daltons) will produce a cardioprotective pyridone with favorable pharmacological properties. PEGylation has been shown to be an effective method to improve the pharmacokinetic profile of small molecules. We have shown that PEGylated-Pirfenidone maintains its immunomodulatory effect on B cells in vitro and has prolonged half-life after IV administration in vivo. We have secured IP on PEGylated-Pirfenidone. In this Phase I application, we seek support to optimize the pharmacokinetics of PEGylated Pirfenidone through highly targeted medicinal chemistry modifications and in vivo measurements in mice, and to test the cardioprotective effects of PEGylated Pirfenidone in clinically relevant in vivo murine models of acute heart injury. In Phase II we will refine the properties of the lead PEGylated compound, characterize its cardioprotective effects in large animal models, and perform initial toxicology studies in preparation of Investigational New Drug(IND) application. If successful, this project will produce a first in class immunomodulatory small molecule for the treatment of acute heart damage and for the prevention of injury-induced heart failure. Based on available pre-clinical data on Pirfenidone and on available clinical data on damage induce heart- failure, just in the US such drug would be expected to save >16,000 lives and >3$bn in projected cost of care every year.